The present invention relates to pharmaceutical compositions of nitrites and the medical use of these compositions.
Nitric oxide (NO) serves as a neurotransmitter between nerve cells and has a general role in redox signaling. Unlike most other neurotransmitters that only transmit information from a presynaptic to a postsynaptic neuron, the small, uncharged, and fat-soluble nitric oxide molecule can diffuse widely and readily enters cells. Thus, it can act on several nearby neurons, even on those not connected by a synapse. At the same time, the short half-life of NO means that such action will be restricted to a limited area, without the necessity for enzymatic breakdown or cellular reuptake. NO is also highly reactive with other free radicals, lipids, and proteins.
NO-cGMP cascade is involved in learning and memory through the maintenance of long-term potentiation (LTP). Thus, NO is an important regulator and mediator of many processes in the brain and a balance in NO levels is critical in maintaining healthy signaling and brain development, and/or maintaining a balance in psychological state.
The role of NO has also been implicated in pain, however it remains unclear as to whether inhibition of NO or production of NO is beneficial in the treatment of pain. In some studies, it has been proposed that several pain-related pathways benefit from the production of NO. In particular, the blood-flow pathway, which is normalized in the presence of NO, may help to decrease ischemic pain; the nerve transmission pathway, which decreases the irritation of the nerves in the synovium, bone, and soft tissues; the opioid receptor pathway, which might stimulate the body's normal pain reduction pathways; and the anti-inflammation pathway. Other studies proposed that the inhibition of NO is beneficial in the treatment of pain. In these studies, NO is believed to be involved in the activation of cyclooxygenase 1 (COX-1) and regulation of cyclooxygenase 2 (COX-2) expression in inflammatory responses to increase prostaglandin release thereby inducing peripheral hyperalgesia and inflammation. NO generated by activation of N-methyl-D-aspartate (NMDA) receptors has been implicated in synaptic plasticity and many of these mechanisms are involved in central sensitization, a common problem in chronic pain. Certain studies have also suggested that NO mediates the peripheral and central anti-nociceptive effects of analgesic compounds such as opioids, and nonsteroidal anti-inflammatory drugs.
Accordingly, there is a continuing need to understand the biological functions of NO and to investigate therapeutic strategies that provide a source of NO for maintaining normal brain functions and for the treatment and/or reduction of pain.